title: Inhibitory effect of TNF-α on malaria pre-erythrocytic stage development: influence of host hepatocyte/parasite combinations.
abstract: BACKGROUND
  The liver stages of malaria parasites are inhibited by cytokines such as interferon-γ or Interleukin (IL)-6. Binding of these cytokines to their receptors at the surface of the infected hepatocytes leads to the production of nitric oxide (NO) and radical oxygen intermediates (ROI), which kill hepatic parasites. However, conflicting results were obtained with TNF-α possibly because of differences in the models used. We have reassessed the role of TNF-α in the different cellular systems used to study the Plasmodium pre-erythrocytic stages.
  
  
  RESULTS
  Human or mouse TNF-α were tested against human and rodent malaria parasites grown in vitro in human or rodent primary hepatocytes, or in hepatoma cell lines. Our data demonstrated that TNF-α treatment prevents the development of malaria pre-erythrocytic stages. This inhibitory effect however varies with the infecting parasite species and with the nature and origin of the cytokine and hepatocytes. Inhibition was only observed for all parasite species tested when hepatocytes were pre-incubated 24 or 48 hrs before infection and activity was directed only against early hepatic parasite. We further showed that TNF-α inhibition was mediated by a soluble factor present in the supernatant of TNF-α stimulated hepatocytes but it was not related to NO or ROI. Treatment TNF-α prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified.
  
  
  CONCLUSIONS
  Treatment TNF-α prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified. However, the nature of the cytokine-host cell-parasite combination must be carefully considered for extrapolation to the human infection.
authors.affiliation: Institut Cochin, Département d'Immunologie, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Nadya
authors.initials: N
authors.lastname: Depinay
authors.forename: Jean Francois
authors.initials: JF
authors.lastname: Franetich
authors.forename: Anne Charlotte
authors.initials: AC
authors.lastname: Grüner
authors.forename: Marjorie
authors.initials: M
authors.lastname: Mauduit
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Chavatte
authors.forename: Adrian J F
authors.initials: AJ
authors.lastname: Luty
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: van Gemert
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Siksik
authors.forename: Laurent
authors.initials: L
authors.lastname: Hannoun
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Georges
authors.initials: G
authors.lastname: Snounou
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D022781:Hepatocytes / Q000187:drug effects / Q000469:parasitology*; D006790:Host-Parasite Interactions / Q000187:drug effects*; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects*; D008288:Malaria / Q000469:parasitology*; D051379:Mice; D009569:Nitric Oxide / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D060225:Tetraspanin 28; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; C554799:Cd81 protein, mouse; D017382:Reactive Oxygen Species; D060225:Tetraspanin 28; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide